Heretofore, many methods for producing a chroman compound such as chromancarboxylic acid have been disclosed. For example, disclosed are a multi-step method employing starting materials including a phenol and an unsaturated carbonyl compound (see, for example, Patent Document 1); a method in which a phenol, a formaldehyde, and an unsaturated compound are allowed to react at 160 to 250° C. in hydrocarbon or halogenated aromatic hydrocarbon serving as a solvent (see, for example, Patent Document 2); a method in which a phenol, a formaldehyde, and an unsaturated compound are allowed to react in the presence of a secondary amine or an acid (see, for example, Patent Document 3); a two-step method (improved method of those disclosed in Patent Documents 2 and 3) including allowing a phenol, a formaldehyde, and an alcohol to react in the presence of an acid or a secondary amine, removing the secondary amine to the outside of the reaction system, and reacting the mixture with an unsaturated compound (see, for example, Patent Document 4); and a method in which a phenol, a formaldehyde, and an unsaturated compound are allowed to react in the presence of an acid (see, for example, Patent Document 5).
The method disclosed in Patent Document 1 requires many reaction steps for producing a target compound, and the time and the number of the steps should be reduced. Thus, the method is not suited for industrial production. The method disclosed in Patent Document 2 is a single-step process employing no catalyst, through which a chroman compound can be produced in a simple manner. However, the method for producing chromancarboxylic acid or a chromancarboxylic acid ester attains insufficient target yield. The method disclosed in Patent Document 3 employs an acid or an amine serving as a catalyst so as to enhance the product yield that has been attained through the method of Patent Document 2. However, when the target is chromancarboxylic acid, the target yield is poor, and large amounts of by-products are formed. In the method disclosed in Patent Document 4, reaction is carried out in two separate steps. Therefore, the method is cumbersome due to additional steps such as removal of catalyst. The method disclosed in Patent Document 5 produces a chromancarboxylic acid ester in the presence of acid. Although the method improves the yield of a chromancarboxylic acid ester to 60%, the yield is still insufficient, raising demand for further improvement.
In the methods disclosed in Patent Documents 2, 4, and 5, an acid serving as a catalyst is added in a considerably large amount; i.e., an amount of about 0.5 equivalents with respect to a phenol serving as a substrate, in an attempt to enhance rate of reaction and selectivity. As a result, apparatuses employed in the methods are corroded by a large amount of acid at high temperature, and complicated countermeasures must be taken for the apparatuses. Thus, these methods raise further problems to be solved for carrying out the method on an industrial scale.
As described hereinabove, each of these methods for synthesizing a chroman compound has both merits and demerits and still has problems when applied on an industrial scale. Particularly when the target is a drug or health food, a high-purity compound must be produced at the lowest possible cost. Heretofore, through a conventional technique, high-purity chroman compounds, particularly chromancarboxylic acid derivatives, cannot be produced at high yield in simple operational steps on an industrial scale.
Patent Document 1: U.S. Pat. No. 4,026,907
Patent Document 2: Japanese Patent Application Laid-Open (kokai) No. 60-92283
Patent Document 3: Japanese Patent Application Laid-Open (kokai) No. 7-97380
Patent Document 4: Japanese Patent Application Laid-Open (kokai) No. 11-80147
Patent Document 5: Japanese Patent Application Laid-Open (kokai) No. 2003-146981